Method for on-demand contraception

ABSTRACT

The invention relates to a method for on-demand contraception, which method comprises administering a progestogen agent or progesterone receptor modulator, such as 17a-acetoxy-11b-[4-N, N-dimethylamino-phenyl)-19-norpregna-4, 9-diene-3, 20-dione (ulipristal acetate) in a woman, within 72 hours before an intercourse or within 120 hours after the intercourse.

The present invention relates to methods for on-demand contraception ina woman, especially women who do not have a regular sexual activity.

TECHNICAL BACKGROUND OF THE INVENTION

Hormonal contraception is considered the most reliable method ofreversible contraception today. It requires the continuous taking ofpills, generally daily, regardless of the frequency of intercourses. Forwomen with infrequent sexual intercourse, however, preparations that aredependent on coitus and thus can be taken less often, with reducedexposure to the effective ingredients, would be more advantageous.Although recognized for a long time (Canzler et al, Zbl. Gynäkol, 1984,106:1182-1191), the need for such on-demand contraception remains unmet(Aitken et al, Contraception, 2008, 78:S28-S35).

Women are actually creating such methods themselves out of existingproducts. In Ghana, a study conducted in 2003 reported that women wereusing norethindrone tablets, marketed for treatment of variousgynecologic problems, as an “on demand” oral contraceptive. Morerecently, anecdotal reports and data collected by colleagues at FamilyHealth International indicate that women in other parts of Africa andelsewhere are deliberately using emergency contraceptive pills in thismanner.

Although oral methods do not provide protection against sexuallytransmitted infections, studies conducted several decades ago reportedthat various doses of levonorgestrel used as a regular postcoitalcontraceptive may provide protection with an efficacy comparable to theoverall efficacy of condoms and other barrier methods in typical use(United Nations Development Programme/United Nations PopulationFund/World Health Organization/World Bank Special Programme of Research,Development and Research Training in Human Reproduction, Task Force onPost-Ovulatory Methods of Fertility Regulation. Efficacy and sideeffects of immediate postcoital levonorgestrel used repeatedly forcontraception. Contraception 2000;61:303-8). It was further proposed toevaluate whether a single vaginal administration of levonorgestrel gelprior to intercourse would interfere with the ovulatory process. (Bracheet al, Contraception, 2007; 76:111-116).

Other progestative agents have been used as post-coital emergencycontraception. Emergency contraception (EC) refers to back-up methodsfor contraceptive emergencies which women can use within the first fewdays after unprotected intercourse to prevent an unwanted pregnancy. Forinstance the preclinical studies and the first clinical trials withulipristal acetate, developed by HRA Pharma for emergency contraception,have proved that a single dose of 50 mg of ulipristal acetate is safeand efficacious when administered to women seeking emergencycontraception within 72 hours after unprotected intercourse (Creinin etal, 2006, Obstetrics and Gynecology, 108(5):1089-1097).

SUMMARY OF THE INVENTION

The invention provides a method for contraception, which methodcomprises on-demand administering a progestogen agent or a progesteronereceptor modulator in a woman, within 72 hours before an intercourse,which administration can be repeated at least once a week.

The invention also provides a method for contraception, comprisingon-demand administering a progestogen agent or a progesterone receptormodulator thereof in a woman, within 120 hours after an intercourse,preferably at least twice a month.

In a preferred embodiment, the invention provides a method forcontraception, which method comprises on-demand administering aprogestogen agent or a progesterone receptor modulator thereof, such as17a-acetoxy-11b-[4-N, N-dimethylamino-phenyl)-19-norpregna-4, 9-diene-3,20-dione (ulipristal acetate) or a metabolite thereof, in a woman,within 72 hours before an intercourse, which administration can berepeated at least once a week.

The invention also provides a method for contraception, comprisingon-demand administering a progestogen agent or a progesterone receptormodulator thereof, such as 17a-acetoxy-11b-[4-N,N-dimethylamino-phenyl)-19-norpregna-4, 9-diene-3, 20-dione (ulipristalacetate) or a metabolite thereof, in a woman, within 120 hours after anintercourse, preferably at least twice a month.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have studied whether ulipristal acetate could be used notonly as an emergency contraceptive, but also as a regular hormonalcontraceptive.

For that purpose, health cycling volunteers received 3 months ofcontinuous daily administration of ulipristal acetate (2.5, 5, or 10 mg)or placebo.

Assessment of ovarian hormones, follicular development, endometrialhistology, and menstrual bleeding patterns was carried out during thethird month of treatment.

One patient (treated with 10 mg of ulipristal acetate/day) missed 2 daysof drug in her third treatment cycle (days 1 and 2) and yet had no signof luteal activity or ovulation. This made the inventors think thatulipristal acetate could be used as a contraceptive which could be takenon-demand, rather than everyday as any hormonal contraceptive pill.

On this basis, the invention provides a method for on-demandcontraception, which method comprises administering a progestogen agentor progesterone receptor modulator, such as 17a-acetoxy-11b-[4-N,N-dimethylamino-phenyl)-19-norpregna-4, 9-diene-3, 20-dione (ulipristalacetate) or a metabolite thereof, in a woman, within 72 hours before anintercourse, and/or within 120 hours after an intercourse.

The invention further provides a method for contraception, which methodcomprises discontinuously administering a progestogen agent orprogesterone receptor modulator, such as ulipristal acetate or ametabolite thereof, in a woman. More particularly the progestogen agentor progesterone receptor modulator, such as ulipristal acetate or ametabolite thereof, may be administered less than once a day during themenstrual cycle. Preferably it is administered at least once a weekduring the menstrual cycle.

More generally, the inventors propose to use progestogen agents orprogesterone receptor modulators for on-demand contraception.

Progestogen Agents:

The progestogen agents, also designated progestins, may be anyprogestationally active compound.

The progestogen agents may be selected from progesterone and itsderivatives such as, for example, 17-hydroxy progesterone esters,19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosterone andderivatives thereof, 17α-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, DL-norgestrel,D-17α-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en-3-one oxime, gestodene,desogestrel, norgestimate, nestorone and drospirenone.

In a preferred embodiment, it is to be understood that the progestogenagent is not combined with any other hormonal contraceptive agent, suchas an estrogen. In that case, the contraceptive is often referred to asa “progestin-only” contraceptive.

Progesterone Receptor Modulators:

Progesterone receptor modulators for use in the present invention may beselected from e.g., ulipristal acetate, mifepristone or CDB-4124 oractive metabolites thereof.

The preferred progesterone receptor modulator is ulipristal acetate.

Ulipristal acetate, formerly known as CDB-2914, is 17α-acetoxy-11β-[4-N,N-dimethylamino-phenyl)-19-norpregna-4, 9-diene-3, 20-dione, representedby formula I:

It is a well-known steroid, more specifically a 19-norprogesterone,which possesses antiprogestational and antiglucocorticoidal activity.This compound, and methods for its preparation, are described in U.S.Pat. Nos. 4,954,490, 5,073,548, and 5,929,262, and international patentapplications WO2004/065405 and WO2004/078709. Properties of thiscompound are further described in Blithe et al, 2003, Steroids,68:1013-1017 and Gainer and Ulmann, 2003, Steroids, 68:1005-1011.

Metabolites of CDB-2914, include those described in Attardi et al,Journal of Steroid Biochemistry & Molecular Biology, 2004, 88: 277-288,e.g. monodemethylated CDB-2914 (CDB-3877); didemethylated CDB-2914(CDB-3963); 17alpha-hydroxy CDB-2914 (CDB-3236); aromatic A-ringderivative of CDB-2914 (CDB-4183).

On-demand:

The subject or patient can be any human female. The invention providesan “on-demand contraception”, which means that the woman may take aprogestogen agent or progesterone receptor modulator, e.g. ulipristalacetate or a metabolite thereof at any time when needed, i.e. when anintercourse is expected, or has recently occurred.

Preferably, the woman does not use any other hormonal contraceptivemedication. In another preferred embodiment, the subject does not useany protection (condom, uterine device, spermicide, etc).

The woman may want to use the progestogen agent or progesterone receptormodulator, e.g. ulipristal acetate or a metabolite thereof, as a regularcontraceptive when her sexual activity becomes more regular. Preferablythe administration is then repeated at least once a week, preferablyonce a week or four times during a menstrual cycle, or twice during amenstrual cycle, or three times during a menstrual cycle. The term«repeated» means that one dosage unit of the progestogen agent orprogesterone receptor modulator, e.g. ulipristal acetate or a metabolitethereof, is administered twice or more, during the menstrual cycle.

In any event, the woman always uses the progestogen agent orprogesterone receptor modulator, e.g. ulipristal acetate or a metabolitethereof on-demand, and not on a daily basis, and preferably not morethan ten days in a row, preferably not more than nine, eight, seven,six, five, four, three or two days in a row. Preferably the progestogenagent or progesterone receptor modulator, e.g. ulipristal acetate or ametabolite thereof is not administered more than four days, three or twodays in a row.

Routes of Administration:

The progestogen agent or progesterone receptor modulator, e.g.ulipristal acetate or a metabolite thereof may be administered by anyconvenient route, including oral, buccal, sublingual, parenteral,transdermal, vaginal, rectal, etc.

For a brief review of present methods for drag delivery, see, Langer,Science 249:1527-1533 (1990), which is incorporated herein by reference.Methods for preparing described in more detail in, for example,Remington's Pharmaceutical Science, 17th Ed., Mack Publishing Company,Easton, Pa. (1985), which is incorporated herein by reference, and whichis hereinafter referred to as “Remington.”

Unit dosages of immediate-release formulations are preferred.

For solid compositions, conventional nontoxic solid carriers may be usedwhich include, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharine, talcum, cellulose,glucose, sucrose. For oral administration, a pharmaceutically acceptablenontoxic composition is formed by incorporating any of the normallyemployed excipients, such as those carriers previously listed.

Oral solid dosage forms are preferentially compressed tablets orcapsules. Compressed tablets may contain diluents to increase the bulkof the progestogen agent or progesterone receptor modulator so thatproduction of a compressed tablet of practical size is possible.Binders, which are agents which impart cohesive qualities to powderedmaterials may be also necessary. Povidone, starch, gelatin, sugars suchas lactose or dextrose, and natural and synthetic gums may be used.Disintegrants are generally necessary in the tablets to facilitatebreak-up of the tablet. Disintegrants include starches, clays,celluloses, algins, gums and crosslinked polymers. Lastly small amountsof material known as lubricant and glidants are included in the tabletsto prevent adhesion of the tablet material to surfaces in themanufacturing process and to improve the flow characteristics of thepowder material during manufacture. Colloidal silicon dioxide is mostcommonly used as a glidant and compounds such as talc, magnesiumstearate or stearic acids are most commonly used as lubricants.Procedures for the production and manufacture of compressed tablets arewell known by those skilled in the art (See Remington).

Capsules are solid dosage forms using preferentially either a hard orsoft gelatin shell as a container for the mixture of the progestogenagent or progesterone receptor modulator and inert ingredients.Procedures for production and manufacture of hard gelatin and softelastic capsules are well known in the art (See Remington).

Buccal or sublingual forms or devices are also useful.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compounds and a sterile vehicle, water being preferred.The progestogen agent or progesterone receptor modulator, depending onthe vehicle and concentration used, can be either suspended or dissolvedin the vehicle. In preparing solutions the compound can be dissolved inwater for injection and filtered sterilized before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anesthetic, preservative and buffering agents can be dissolvedin the vehicle. To enhance the stability, the composition can be frozenafter filling into the vial and the water removed under vacuum. The drylyophilized powder is then sealed in the vial and an accompanying vialof water for injection is supplied to reconstitute the liquid prior touse. Parenteral suspensions can be prepared in substantially the samemanner except that the compounds are suspended in the vehicle instead ofbeing dissolved and sterilization cannot be accomplished by filtration.The compound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the progestogen agent or progesterone receptormodulator.

Additionally, a suppository or a pessary can be employed to deliver theprogestogen agent or progesterone receptor modulator. The activecompound can be incorporated into any of the known suppository bases bymethods known in the art. Examples of such bases include cocoa butter,polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate,and mixtures of these with other compatible materials to modify themelting point or dissolution rate. These suppositories can weight fromabout 1 to 2.5 gm.

Transdermal delivery systems comprising penetration enhancer and anocclusive backing are of use to deliver the progestogen agent orprogesterone receptor modulator. Examples of penetration enhancersinclude dimethyl sulfoxide, dimethyl acetamide and dimethylformamide.Transcutenous gels may be advantageous too. Examples of such gels aredescribed e.g. in U.S. Pat. No. 5,904,931.

The progestogen agent or progesterone receptor modulator may beadministered by vaginal route, for instance in the form of a gel or avaginal device.

In another embodiment, the method of the invention comprises on-demandinserting a vaginal device, such as a vaginal ring that releases theprogestogen agent or progesterone receptor modulator, in a woman, within24 hours before or after an intercourse.

The vaginal ring usually comprises a synthetic polymer, which can be asilicone elastomer or a non-silicone resin. In a particular embodimentthe ring comprises a polymer core, surrounded by an outer polymer layercomprising the progestogen agent or progesterone receptor modulator. Ina particular embodiment, the ring is as described in internationalpatent application WO2006/010097.

Preferably, the vaginal ring is removed within 12 hours after theintercourse. Most preferably, the vaginal ring is maintained in placefor a minimum of 6 to 12 hours.

The oral route is preferred. Other routes of administration can besuitable in comparison with oral routes using blood levels to provideclinical success.

Dosages

The unit dosage of the progestogen agent or progesterone receptormodulator, e.g. ulipristal acetate or a metabolite thereof, may bebetween 10 and 40 mg, preferably 20 mg or 30 mg. Preferably the unitdosage of progestogen agent or progesterone receptor modulator, e.g.ulipristal acetate or a metabolite thereof is to be administered orally.

Regimen:

In a first embodiment of the invention, the progestogen agent orprogesterone receptor modulator, e.g. ulipristal acetate or a metabolitethereof, can be administered within 72 hours before an intercourse,preferably within 48 h before the intercourse, more preferably within 24h before the intercourse, still more preferably within 12 before theintercourse.

In a second embodiment of the invention, the progestogen agent orprogesterone receptor modulator, e.g. ulipristal acetate or a metabolitethereof can be administered within 120 hours after an intercourse,preferably within 72 h after the intercourse, more preferably within 48h after the intercourse, still more preferably within 24 h after theintercourse, even more preferably within 12 h after the intercourse.

In a preferred embodiment, the administration is repeated at least twicea month, preferably three times a mouth or once a week.

For optimal efficiency, the two embodiments may be combined, i.e. aprogestogen agent or progesterone receptor modulator, e.g. ulipristalacetate or a metabolite thereof, can be administered within 72 before anintercourse, and the same woman can also take a progestogen agent orprogesterone receptor modulator, e.g. ulipristal acetate or a metabolitethereof, within 120 hours after the intercourse.

The following example is provided by way of illustration only and not byway of limitation.

EXAMPLE Multiple Intakes of Ulipristal Acetate Within a Menstrual Cycle

Several women received ulipristal acetate (30 mg) after a declaredintercourse, twice during a menstrual cycle.

No pregnancy was observed.

Patient 1^(st) intake 2^(nd) intake Woman 1 intercourse: intercourse:Dec 11, 2007 Dec 14, 2007 06:00* 21:00 Ulipristal acetate Dec 14, 2007intake: 14:37 Dec 13, 2007 11:25 Woman 2 intercourse: intercourse: Dec12, 2007 Dec 15, 2007 05:00 23:00 Ulipristal acetate Ulipristal acetateintake: intake: Dec 18, 2007 Dec 14, 2007 10:45 11:05 Woman 3intercourse: intercourse: Dec 15, 2007 Dec 14, 2007 06:00 22:00Ulipristal acetate Ulipristal acetate intake: intake: Dec 18, 2007 Dec17, 2007 11:15 11:40 Woman 4 intercourse: intercourse: Dec 14, 2007 Dec07, 2007 01:00 20:00 Ulipristal acetate Ulipristal acetate intake:intake: Dec 12, 2007 Dec 17, 2007 10:58 12:20 Woman 5 intercourse:intercourse: Nov 5, 2007 Nov 2, 2007 06:00 08:00 Ulipristal acetateUlipristal acetate intake: intake: Nov 5, 2007 Nov 8, 2007 15:00 15:30*time are expressed in 24 hours format

1-34. (canceled)
 35. A method for contraception, the method comprisingadministering a progesterone receptor modulator to a woman, within 120hours after an unprotected intercourse.
 36. The method of claim 35,wherein the progesterone receptor modulator is administered more than 72hours and up to 120 hours after the unprotected intercourse.
 37. Themethod of claim 35, wherein the progesterone receptor modulator is17α-acetoxy-11β3-(4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione (ulipristalacetate) or a metabolite thereof.
 38. The method of claim 35, whereinthe progesterone receptor modulator is administered at a dosage rangingfrom 10 to 40 mg.
 39. The method of claim 35, wherein the progesteronereceptor modulator is administered at a dosage ranging from 20 mg to 30mg.
 40. The method of claim 35, which is repeated at least twice duringa menstrual cycle.
 41. The method of claim 35, wherein theadministration of the progesterone receptor modulator is oral.
 42. Amethod for contraception, the method comprising administering a dosageof 20 mg to 30 mg of ulipristal acetate to a woman within 120 hoursafter an unprotected intercourse.
 43. The method of claim 42, whereinthe administration is oral.
 44. The method of claim 42, whereinulipristal acetate is administered more than 72 hours and up to 120hours after the unprotected intercourse.
 45. The method of claim 42,wherein ulipristal acetate is administered as an oral solid dosage form.46. The method of claim 45, wherein the oral solid dosage form is animmediate-release oral form.